The major goal of this research project is to define the underlying mechanisms of the human autoimmune disease Systemic Lupus Erythematosus (SLE). Pathogenic anti-DNA autoantibodies that cause glomerulonephritis and other autoimmune lesions of SLE can be distinguished by their immunochemical properties, charge and idiotypic profile. The cellular and humoral immunoregulatory imbalances in patients with SLE that specifically induce the production of the select population of pathogenic autoantibodies will be investigated in detail. The specific set of T and B cells responsible for pathogenic autoantibody production will be analyzed by studying both subpopulations and clones. T cell receptor variable region genes expressed by the pathogenic autoantibody inducing T cells will be analyzed and sequenced. The major cross-reactive idiotype(s) shared exclusively or preferentially by the pathogenic autoantibodies will be identified. The cellular and humoral immunoregulatory mechanisms controlling the production of pathogenic autoantibodies bearing the distinctive cross-reactive idiotype (CRI) will be defined by studying lymphocyte subsets and clones. Monoclonal human autoantibodies that share the distinctive CRI of pathogenic anti-DNA autoantibodies will be derived by hybridoma technology. The immunochemistry, spectrotype and antigenic specificity patterns of the CRI+ monoclonal autoantibodies will be studied. The proposed studies will be important for designing specific immunotherapy for rheumatic autoimmune diseases in humans and the experiments will also yield basic information about immunoregulation in humans.